A Novel Human Long Noncoding RNA <i>SCDAL</i> Promotes Angiogenesis through SNF5‐Mediated GDF6 Expression

Wu, Rongrong; Hu, Wangxing; Chen, Huan; Wang, Yingchao; Li, Qingju; Xiao, Changchen; Fan, Lin; Zhong, Zhiwei; Chen, Xiaoying; Lv, Kaiqi; Zhong, Shuhan; Shi, Yanna; Chen, Jinghai; Zhu, Wei; Zhang, Jianyi; Hu, Xinyang

doi:10.1002/advs.202004629

Cited by 14 publications

(10 citation statements)

References 56 publications

(73 reference statements)

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“…These analyses provide novel insights to explore the potential mechanisms underlying HCM progression. LncRNA has been found to regulate cardiomyocyte hypertrophy, apoptosis, angiogenesis, atherosclerosis, and other pathophysiological processes and play an important role in the development of cardiovascular disease (29)(30)(31)(32). In recent years, it has also been reported that lncRNA plays an important role in HCM.…”

Section: Discussionmentioning

confidence: 99%

Identification of key genes for hypertrophic cardiomyopathy using integrated network analysis of differential lncRNA and gene expression

Cao

Liu

2022

Front. Cardiovasc. Med.

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ObjectiveHypertrophic cardiomyopathy (HCM) is a complex heterogeneous heart disease. Recent reports found that long non-coding RNAs (lncRNAs) play an important role in the progression of cardiovascular diseases. The present study aimed to identify the novel lncRNAs and messenger RNAs (mRNAs) and determine the key pathways involved in HCM.MethodsThe lncRNA and mRNA sequencing datasets of GSE68316 and GSE130036 were downloaded from the Gene Expression Omnibus (GEO) database. An integrated co-expression network analysis was conducted to identify differentially expressed lncRNAs and differentially expressed mRNAs in patients with HCM. Then, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were explored to identify the biological functions and signaling pathways of the co-expression network. Protein–protein interaction (PPI) and hub gene networks were constructed by using Cytoscape software. Plasma samples of patients with HCM and the GSE89714 dataset were used to validate the bioinformatics results.ResultsA total of 1,426 differentially expressed long non-coding RNAs (lncRNAs) and 1,715 differentially expressed mRNAs were obtained from GSE68316, of which 965 lncRNAs and 896 mRNAs were upregulated and 461 lncRNAs and 819 mRNAs were downregulated. A total of 469 differentially expressed lncRNAs and 2,407 differentially expressed mRNAs were screened from GSE130036, of which 183 lncRNAs and 1,283 mRNAs were upregulated and 286 lncRNAs and 1,124 mRNAs were downregulated. A co-expression network was constructed and contained 30 differentially expressed lncRNAs and 63 differentially expressed mRNAs, which were primarily involved in ‘G-protein beta/gamma-subunit complex binding,' ‘polyubiquitin modification-dependent protein binding,' ‘Apelin signaling pathway,' and ‘Wnt signaling pathway.' The 10 hub genes in the upregulated network [G Protein Subunit Alpha I2 (GNAI2), G Protein Subunit Alpha I1 (GNAI1), G Protein Subunit Alpha I3 (GNAI3), G Protein Subunit Gamma 2 (GNG2), G Protein Subunit Beta 1 (GNB1), G Protein Subunit Gamma 13 (GNG13), G Protein Subunit Gamma Transducin 1 (GNGT1), G Protein Subunit Gamma 12 (GNG12), AKT Serine/Threonine Kinase 1 (AKT1) and GNAS Complex Locus (GNAS)] and the 10 hub genes in the downregulated network [Nucleotide-Binding Oligomerization Domain Containing Protein 2 (NOD2), Receptor-Interacting Serine/Threonine Kinase 2 (RIPK2), Nucleotide-Binding Oligomerization Domain Containing Protein 1 (NOD1), Mitochondrial Antiviral Signaling Protein (MAVS), Autophagy Related 16-Like 1 (ATG16L1), Interferon Induced With Helicase C Domain 1 (IFIH1), Autophagy Related 5 (ATG5), TANK-Binding Kinase 1 (TBK1), Caspase Recruitment Domain Family Member 9 (CARD9), and von Willebrand factor (VWF)] were screened using cytoHubba. The expression of LA16c-312E8.2 and RP5-1160K1.3 in the plasma of patients with HCM was elevated, and the expression of the MIR22 host gene (MIR22HG) was decreased, which was consistent with our analysis, while the expression of LINC00324 and Small Nucleolar RNA Host Gene 12 (SNHG12) was not significantly different between the two groups. Verification analyses performed on GSE89714 showed the upregulated mRNAs of Chloride Voltage-Gated Channel 7 (CLCN7), N-Acetylglucosamine-1-Phosphate Transferase Subunit Gamma (GNPTG), Unk Like Zinc Finger (UNKL), Adenosine Monophosphate Deaminase 2 (AMPD2), GNAI3, WD Repeat Domain 81 (WDR81), and Serpin Family F Member 1 (SERPINF1) and downregulated mRNAs of TATA-Box Binding Protein Associated Factor 12 (TAF12) co-expressed with five crucial lncRNAs. Moreover, GNAI2, GNAI3, GNG12, and vWF were upregulated and GNAS was downregulated in the top 10 hub genes of upregulated and downregulated PPI networks.ConclusionThese findings from integrative biological analysis of lncRNA-mRNA co-expression networks explored the key genes and pathways and provide new insights into the understanding of the mechanism and discovering new therapeutic targets for HCM. Three differentially expressed pivotal lncRNAs (LA16c-312E8.2, RP5-1160K1.3, and MIR22HG) in the co-expression network may serve as biomarkers and intervention targets for the diagnosis and treatment of HCM.

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Section: Discussionmentioning

confidence: 99%

Identification of key genes for hypertrophic cardiomyopathy using integrated network analysis of differential lncRNA and gene expression

Cao

Liu

2022

Front. Cardiovasc. Med.

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“…It is a cardiac dysfunction or organic disease caused by coronary artery stenosis and insufficient blood supply (1,2). Reducing cardiomyocyte apoptosis and promoting angiogenesis are both important means to improve the function of ischemic myocardium and improve the prognosis of infarcted myocardium (3)(4)(5).…”

Section: Discussionmentioning

confidence: 99%

“…It is well known that, preventing cardiomyocytes apoptosis reduces the myocardium injury induced by hypoxia/ischemia (3). Other studies also demonstrated that compensatory angiogenesis and establishment of bilateral blood supply after MI recover blood perfusion and improve cardiac function (4,5). However, the key proteins and key pathways that affect angiogenesis and cardiomyocyte apoptosis for improving the prevention, treatment, and prognosis of MI are still not very clear.…”

Section: Introductionmentioning

confidence: 99%

TXNIP knockout improves cardiac function after myocardial infarction by promoting angiogenesis and reducing cardiomyocyte apoptosis

Wang¹,

Wang²,

Zhang³

et al. 2022

Cardiovasc Diagn Ther

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Background: Myocardial infarction (MI) is a common cause of death. Thioredoxin-interacting protein (TXNIP) expression increases after MI, and it exerts a negative regulatory effect on cardiac function after MI. Our study aimed to investigate the specific regulatory mechanism of TXNIP on angiogenesis and cardiomyocyte apoptosis after MI. Methods:The TXNIP gene knock-in (TXNIP-KI) and knock-out (TXNIP-KO) mice were generated, respectively. Eight-week-old male TXNIP-KO, TXNIP-KI, and wild type (WT) mice were subjected to MI by permanent ligation of the left anterior descending artery. Cardiomyocyte apoptosis was detected by TUNEL assay on the 4th post-surgery day. The expressions of TXNIP, hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), phosphorylated protein kinase B (p-AKT), p-AMP-activated protein kinase (p-AMPK), cleaved caspase-3, and caspase-3 were detected by Western blot. Quantitative real-time PCR was performed to detect the expression of TXNIP, HIF-1α, VEGF, prolyl hydroxylase (PHD) 1, and factor inhibiting HIF (FIH). In addition, the superoxide dismutase (SOD) activity and malondialdehyde (MDA) level in each group were also measured. On day 7 after MI, the hearts of sacrificed animals were analyzed by immunohistochemistry to assess CD31 expression and determine the density of angiogenesis. One month after treatment, the cardiac functional and structural changes were determined by echocardiography and the level of myocardial fibrosis was observed by Masson staining.Results: Compared with WT mice, TXNIP-KO mice had a significantly improved cardiac functional recovery after MI, and the proportion of myocardial fibrosis area was dramatically reduced, cardiomyocyte apoptosis was decreased, and angiogenesis was significantly increased; TXNIP-KI mice reversed in these changes. The expression of HIF-1α, p-AKT, and p-AMPK increased after MI in TXNIP-KO mice, and the mRNA expression of PHD 1 and FIH decreased. TXNIP-KI mice reversed in these changes.Conclusions: After MI, TXNIP down-regulated the level of HIF-1α and VEGF, reduced the number of angiogenesis, increased cardiomyocyte apoptosis, and ultimately led to a poor prognosis of ischemic myocardium. TXNIP was a protein with negative effects after MI and was expected to be a target for the prevention and treatment of MI.

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“…TNK2 Antisense RNA 1 (TNK2-AS1), a protein-modifying lncRNA, promotes angiogenesis via STAT3/VEGF and is upregulated in cancer [ 43 , 44 ]. In contrast, neuroblastoma-associated transcript 1 (NBAT1), which interacts with Sox9 and reduces its protein stability, resulting in anti-angiogenesis [ 45 ], is downregulated in gastric cancer ( Figure 3 ) [ 45 , 46 ]. Similarly, the encoding peptide LINC00908 has an anti-angiogenic effect.…”

Section: Functional Mechanisms Of Lncrnas In Angiogenesismentioning

confidence: 99%

LncRNAs and the Angiogenic Switch in Cancer: Clinical Significance and Therapeutic Opportunities

Mabeta

Hull

Dlamini

2022

Genes

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Angiogenesis is one of the hallmarks of cancer, and the establishment of new blood vessels is vital to allow for a tumour to grow beyond 1–2 mm in size. The angiogenic switch is the term given to the point where the number or activity of the pro-angiogenic factors exceeds that of the anti-angiogenic factors, resulting in the angiogenic process proceeding, giving rise to new blood vessels accompanied by increased tumour growth, metastasis, and potential drug resistance. Long noncoding ribonucleic acids (lncRNAs) have been found to play a role in the angiogenic switch by regulating gene expression, transcription, translation, and post translation modification. In this regard they play both anti-angiogenic and pro-angiogenic roles. The expression levels of the pro-angiogenic lncRNAs have been found to correlate with patient survival. These lncRNAs are also potential drug targets for the development of therapies that will inhibit or modify tumour angiogenesis. Here we review the roles of lncRNAs in regulating the angiogenic switch. We cover specific examples of both pro and anti-angiogenic lncRNAs and discuss their potential use as both prognostic biomarkers and targets for the development of future therapies.

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A Novel Human Long Noncoding RNA SCDAL Promotes Angiogenesis through SNF5‐Mediated GDF6 Expression

Cited by 14 publications

References 56 publications

Identification of key genes for hypertrophic cardiomyopathy using integrated network analysis of differential lncRNA and gene expression

Identification of key genes for hypertrophic cardiomyopathy using integrated network analysis of differential lncRNA and gene expression

TXNIP knockout improves cardiac function after myocardial infarction by promoting angiogenesis and reducing cardiomyocyte apoptosis

LncRNAs and the Angiogenic Switch in Cancer: Clinical Significance and Therapeutic Opportunities

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